David Gregory, Turner Garth M, Yao Yao, Protopopov Alexei, DePinho Ronald A
Departments of Medical Oncology, Medicine, and Genetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes Dev. 2003 Oct 1;17(19):2396-405. doi: 10.1101/gad.1109403.
The histone code guides many aspects of chromosome biology including the equal distribution of chromosomes during cell division. In the chromatin domains surrounding the centromere, known as pericentric heterochromatin, histone modifications, particularly deacetylation and methylation, appear to be essential for proper chromosome segregation. However, the specific factors and their precise roles in this highly orchestrated process remain under active investigation. Here, we report that germ-line or somatic deletion of mSds3, an essential component of the functional mSin3/HDAC corepressor complex, generates a cell-lethal condition associated with rampant aneuploidy, defective karyokinesis, and consequently, a failure of cytokinesis. mSds3-deficient cells fail to deacetylate and methylate pericentric heterochromatin histones and to recruit essential heterochromatin-associated proteins, resulting in aberrant associations among heterologous chromosomes via centromeric regions and consequent failure to properly segregate chromosomes. Mutant mSds3 molecules that are defective in mSin3 binding fail to rescue the mSds3 null phenotypes. On the basis of these findings, we propose that mSds3 and its associated mSin3/HDAC components play a central role in initiating the cascade of pericentric heterochromatin-specific modifications necessary for the proper distribution of chromosomes during cell division in mammalian cells.
组蛋白密码指导染色体生物学的许多方面，包括细胞分裂过程中染色体的均匀分布。在着丝粒周围的染色质结构域，即所谓的着丝粒周围异染色质中，组蛋白修饰，特别是去乙酰化和甲基化，似乎对于正确的染色体分离至关重要。然而，在这个高度协调的过程中，具体因素及其精确作用仍在积极研究中。在这里，我们报告功能性mSin3/HDAC共抑制复合物的一个重要组成部分mSds3的生殖系或体细胞缺失会产生一种细胞致死状态，伴有大量非整倍体、有缺陷的核分裂，进而导致胞质分裂失败。mSds3缺陷细胞无法使着丝粒周围异染色质组蛋白去乙酰化和甲基化，也无法募集必需的异染色质相关蛋白，导致异源染色体通过着丝粒区域异常关联，从而无法正确分离染色体。在mSin3结合方面有缺陷的突变型mSds3分子无法挽救mSds3缺失的表型。基于这些发现，我们提出mSds3及其相关的mSin3/HDAC成分在启动着丝粒周围异染色质特异性修饰的级联反应中起核心作用，这对于哺乳动物细胞分裂过程中染色体的正确分布是必需的。
